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This article discusses a case of a rare lung tumor called stratified bronchiolar adenoma. The tumor was found in a 67-year-old woman with no history of smoking. The tumor was composed of stratified epithelial cells and was accompanied by an EGFR exon 20 insertion. Immunofluorescence analysis showed that the tumor cells in the basal area coexpressed p40 and TTF-1, while those in the apical area expressed only TTF-1. The authors argue that this tumor should be described as stratified bronchiolar adenoma rather than a squamous cell neoplasm. Further research is needed to understand the origin and clinical importance of this tumor. [Extracted from the article]

Multiplex immunohistochemistry/multiplex immunofluorescence (mIHC/mIF) enables the simultaneous detection of multiple markers in a single tissue section by visualizing the markers in different colors. Currently, tyramide signal amplification (TSA) is the most commonly used method because it is heat resistant to multiplexing. SPiDER-βGal (6′-(diethylamino)-4′-(fluoromethyl)spiro[isobenzofuran-1(3H),9′-[9H]xanthen]-3′-yl β-d-galactopyranoside), a novel fluorogenic substrate of β-galactosidase (β-gal) was reported recently. Its properties are favorable for application in sensitive mIF based on quinone methide chemistry. Combining SPiDER-βGal with its related substrates, a novel, sensitive fluorescent IHC method for formalin-fixed paraffin-embedded (FFPE) sections was developed, named the galactosidase-catalyzed fluorescence amplification method (GAFAM). Evaluation of GAFAM indicated the following characteristics: (1) the entire GAFAM procedure was complete within a few hours; (2) the optimal working concentration of the substrates was 20 μM; (3) the fluorescent product was heat resistant; (4) the GAFAM exhibited sensitivity comparable with that of TSA, which was higher than that of conventional IF; and (5) the GAFAM was applicable to mIF and multispectral imaging. GAFAM is expected to be applicable to IF (or mIF in combination with TSA), and is a promising tool for facilitating morphological research in various fields of life science. [ABSTRACT FROM AUTHOR]

Desmoid‐type fibromatosis (DF) is a locally aggressive but non‐metastatic (myo)fibroblastic neoplasm. A hallmark of the tumor is nuclear positivity for beta‐catenin in immunohistochemistry due mostly to CTNNB1 mutations. However, a recent study has reported that even beta‐catenin 'nuclear‐negative' DFs can harbor CTNNB1 mutations and that the positive ratio of nuclear beta‐catenin in DF is different among antibodies. Here, we reviewed soft tissue lesions for which the possibility of DF was considered and compared the sensitivity and specificity of nuclear beta‐catenin for the diagnosis of DF among commonly used anti‐beta‐catenin antibodies, i.e., clone beta‐catenin 1, 17C2 and 14. We analyzed 26 cases of DF, 28 cases of benign fibroblastic lesions, and 27 cases of other soft tissue tumors. The sensitivity and specificity of nuclear beta‐catenin for the diagnosis of DF were different among antibodies; 54% and 98% in clone beta‐catenin 1, 85% and 84% in 17C2, and 96% and 62% in 14. IHC of LEF1 showed comparable results with IHC of beta‐catenin, with a sensitivity of 88% and specificity of 76%. Additionally, when beta‐catenin 1 was used, DFs showed characteristic dotted cytoplasmic staining, often appearing as rings. Our results might be helpful for making a correct diagnosis of DF. [ABSTRACT FROM AUTHOR]

T-cell recruitment to skin tissues is essential for inflammation in different cutaneous diseases; however, the mechanisms by which these T cells access the skin remain unclear. High endothelial venules expressing peripheral node address in (PNAd), an L-selectin ligand, are located in secondary lymphoid organs and are responsible for increasing T-cell influx into the lymphoid tissues. They are also found in non-lymphoid tissues during inflammation. However, their presence in different common inflammatory cutaneous diseases and their correlation with T-cell infiltration remain unclear. Herein, we explored the mechanisms underlying the access of T cells to the skin by investigating the presence of PNAd-expressing vessels in different cutaneous diseases, and its correlation with T cells' presence. Skin sections of 43 patients with different diseases were subjected to immunohistochemical and immunofluorescence staining to examine the presence of PNAd-expressing vessels in the dermis. The correlation of the percentage of these vessels in the dermis of these patients with the severity/grade of CD3+ T-cell infiltration was assessed. PNAd-expressing vessels were commonly found in the skin of patients with different inflammatory diseases. A high percentage of these vessels in the dermis was associated with increased severity of CD3+ T-cell infiltration (P < 0.05). Additionally, CD3+ T cells were found both around the PNAd-expressing vessels and within the vessel lumen. PNAd-expressing vessels in cutaneous inflammatory diseases, characterized by CD3+ T-cell infiltration, could be a crucial entry point for T cells into the skin. Thus, selective targeting of these vessels could be beneficial in cutaneous inflammatory disease treatment. In our study, we observed that PNAd-expressing vessels, identified as a crucial gateway for CD3+ T-cell entry into secondary lymph nodes, are a hallmark feature in the dermis across various CD3+ T-cell-mediated cutaneous diseases. This observation correlates with the extent of CD3+ T-cell infiltration within these conditions, suggesting that PNAd-expressing vessels may serve as a critical conduit for CD3+ T cells into the skin. Graphical Abstract [ABSTRACT FROM AUTHOR]

Methyl halides released from the ocean serve as important carriers of halogen into the atmosphere. The transported halogens are released into the atmosphere through photolysis, and catalyze ozone depletion. Marine bacteria are known to be a source of methyl halides in marine environments, but the effects of environmental temperature on the production of methyl halides by bacteria have not been studied. Here, we examined the effect of temperature on methyl halide production in a culture of marine bacteria (HKF-1) belonging to Erythrobacter , which was incubated for several days at 15 °C, 20 °C, 25 °C, or 30 °C. We also analyzed the effect of temperature on the production of methyl halides in a culture of the marine γ -proteobacterium Pseudomonas stutzeri . The concentrations of methyl halides such as CH 3 Cl, CH 3 Br, and CH 3 I in the gas phase above cultured samples were determined using dynamic headspace gas chromatography–mass spectrometry. Bacterial growth was monitored by measuring the optical density at 600 nm. The production rate of CH 3 Cl by marine bacteria (HKF-1) was increased with increasing temperature from 15 °C to 30 °C, and the maximum production rate for CH 3 Cl was ~ 19 pmol (10 9 cells) − 1 d − 1 at 30 °C, which was about 26 times higher than that at 15 °C (~ 0.7 pmol (10 9 cells) − 1 d − 1 ). The production rates of CH 3 Cl by P. stutzeri were also increased with increasing temperature from 15 °C to 30 °C. The production rates for CH 3 Br by bacteria (HKF-1) were increased with increasing temperature from 15 °C to 30 °C, whereas changes in the production rates for CH 3 I by these two bacteria were relatively small during the temperature rise from 15 °C to 30 °C. Higher production rates of CH 3 Cl, CH 3 Br, and CH 3 I were observed during the exponential phase than during the stationary phase in the cultures of HKF-1. The ratio of production rates (CH 3 Cl:CH 3 Br:CH 3 I) was 1.0:0.12:0.015 in the cultures of HKF-1, and this ratio was almost constant between 15 °C and 25 °C. These results suggested that water temperature could affect the production of methyl halides derived from bacteria and would be a significant factor for estimating the emissions of methyl halides from marine environments. [ABSTRACT FROM AUTHOR]

The traditional fermented dairy products were collected from three nomadic families in Donto-Govi prefecture in Mongolia (central Mongolia), and those microbiota were analyzed. These samples consist three of ‘airag’, two of ‘tarag’, two of ‘isgelen tarag’ and ‘qoormog’, and some cheeses. In airag, Lactobacillus ( L.) helveticus, L. kefiri, and Saccharomyces ( S.) dairensis were common, and L. paracasei, L. plantarum, L. farciminis, S. cerevisiae, Issachenkia ( I.) orientalis, Kluyveromyces (K.) wickerhamii were also found. In tarag, isgelen tarag and qoormog, L. helveticus, L. kefiri, L. fermentum, L. paracasei and L. acetotolerance were found. L. delbrueckii subsp. bulgaricus was also found in one tarag and one qoormog samples. Randomly amplified polymorphic DNA (RAPD) analysis showed that there were diversity in each L. helveticus family and products, and there were common strains found in airag and tarag in the same family. [ABSTRACT FROM AUTHOR]

Silicon nitride films have been prepared by atmospheric pressure chemical vapor deposition (APCVD) on moving glass substrates from a gas mixture of monosilane, ammonia and nitrogen. The CVD reactor system used in this work is similar to those used in APCVD during a float glass production process (on-line CVD). At the substrate temperature of 830 °C, we prepared silicon nitride films and the deposition rate was over 10 nm/s. The deposition rates measured are not high enough at the temperatures typical of most on-line processes (650–750 °C). The deposition rate and the characteristics of silicon nitride films have been investigated using ellipsometry, X-ray photoemission spectroscopy (XPS) and Rutherford backscattering spectroscopy (RBS). The obtained film is transparent and the refractive index at the wavelength of 550 nm is 1.90–1.97. The film composition depends on the ratio of NH3 to SiH4 in the source gas and the hydrogen concentration is approximately 15%. It seems that hydrogen atoms incorporated in the film affect properties of the films. [Copyright &y& Elsevier]

The capacitance diaphragm gauge (CDG) is one of the most important vacuum gauges in low and medium vacuum ranges. CDG has a non-linear sensitivity below 100 Pa because of the temperature difference between the sensor head and the vacuum chamber, which is called thermal transpiration. This sensitivity depends on gas species and pressure. In this study, by using a direct simulation Monte Carlo (DSMC) method, pressure distribution in the connecting tube of the gauge was obtained under the pressure range from molecular flow regime to viscous flow regime (10−2–102 Pa) taking account of the temperature distribution along the connecting tube. Furthermore, the pressure dependence of the sensitivity of the CDG was derived from the pressure difference between the hot and cold ends, and found to be in good agreement with the pressure dependence of sensitivity obtained by an empirical equation. The influence of gas–surface interaction on the thermal transpiration was also analyzed. [Copyright &y& Elsevier]

As vegetation classification on the highly diverse rangeland is an inevitable procedure in evaluating total forage resources and assessing human impact in large areas, a supervised classification was conducted by satellite image processing using geocoded bands 2, 3 and 4 of Landsat 5 Thematic Mapper (TM) images, dated 13 April 1994 in the Abdal Aziz Mountain study area in northeastern Syria. The rangeland was categorized into six classes according to the plant contacts of dominant shrubs (Artemisia herba-alba and Noaea mucronata) and herbaceous plants. In addition, cultivated fields were categorized into two classes. An average classification accuracy of 85% in the supervised processing and an average ground verification accuracy of 81% on the Landsat-estimated vegetation classes were achieved for the rangeland. These show that a 30m X 30m resolution of the Landsat TM image had the ability to recognize vegetation at six sub-divided community levels, and the successful classification was conducted on the whole rangeland of the study area. The distinctive feature of this work is that this vegetation classification using Landsat TM images was accomplished at the level of classifying a A. herba-alba and N. mucronata dominant community into six sub-community classes. This detailed vegetation classification was conducted with the final aim of forage resource estimation and human impact assessment in mind. [ABSTRACT FROM AUTHOR]

Background: The oncofetal protein insulin‐like growth factor 2 mRNA binding protein‐3 (IMP3) is expressed in various cancers. In this study, we examined the diagnostic utility of IMP3 immunohistochemistry in the context of intravascular large B‐cell lymphoma (IVL). Methods: We obtained 25 skin biopsy (SB) specimens diagnosed as IVL and nine IVL‐negative SB specimens from 27 IVL patients. Additionally, 27 negative SB specimens from 26 non‐IVL patients were obtained from our pathology archives. We performed IMP3 immunohistochemistry on these 61 SB specimens, considering IMP3 expression in any mononuclear cell as positive. In selected cases, triple immunostaining for IMP3, PAX5, and CD34 was performed to analyze the origin and location of IMP3‐positive cells. Results: IMP3 was expressed in most intravascular lymphoma cells in all the 25 SB specimens diagnosed as IVL. Furthermore, our evaluation revealed the presence of intravascular IMP3‐positive B‐cells in five of the nine negative SB specimens from IVL patients; however, this was not observed in the 27 SB specimens from non‐IVL patients. Conclusion: IMP3 was expressed in most IVL cells, and IMP3 immunohistochemistry could serve as a sensitive diagnostic aid for detecting IVL cells in SB. [ABSTRACT FROM AUTHOR]

Dementia is associated with a high risk of death and hospitalization among patients on hemodialysis (HD). We retrospectively evaluated the prevalence of mild cognitive impairment (MCI) in 421 patients on maintenance HD across nine facilities and investigated whether decreased handgrip strength was associated with decreased cognitive function. The Montreal Cognitive Assessment-Japan (MoCA-J) score and handgrip strength were measured. The mean age was 69.8 ± 11.2 years, and the median dialysis vintage 74.5 (IQR 30–150) months. The median MoCA-J score was 25 (IQR 21–27), and MCI was confirmed in 245 (58.2%) patients. Both the MoCA-J score and MoCA-J executive score were associated with age, history of cerebrovascular disease (CVA), and handgrip strength after adjustments. We found, among patients on HD aged under 70 years with a history of CVA, a handgrip strength < 90% (25.2 kg in males and 16.2 kg in females) correlated with significantly lower MoCA-J scores. A high prevalence of MCI and decreased handgrip strength were observed in patients on HD. Handgrip strength may be useful for the easy detection of MCI. A decrease in handgrip strength would allow for the early detection of MCI, especially among patients on HD aged under 70 years with a history of CVA. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgery is the most effective treatment for early-stage lung cancer, but it poses a heavy physical burden. Accordingly, understanding the perioperative daily life conditions of patients is important to maintain their health status and to provide appropriate treatment. We performed a prospective study to examine the socioclinical factors associated with the physical quality of life of patients who underwent surgery for lung cancer at Shonan Kamakura General Hospital, Kanagawa, Japan. In the preoperative setting, living alone and lower performance status were independently associated with worse physical quality of life. In the postoperative setting at 6 months, later smoking cessation, lower performance status, living alone, and higher comorbid burden were independently associated with worse physical quality of life. In order to maintain quality of life and provide enough treatment, perioperative management should include taking care of the patient's physical condition, lifestyle, smoking, and comorbid status. Surgery is the most effective treatment for early-stage lung cancer; however, it poses a higher physical burden than other treatment options. Therefore, understanding the perioperative course of patients is important. Using the Short Form Health Survey 36, we prospectively measured the physical quality of life of patients who underwent anatomical pulmonary resection for non-small cell lung cancer at Shonan Kamakura General Hospital, Kanagawa, Japan (n = 87). In the preoperative setting, patients who had lower performance status and lived alone had significantly worse physical quality of life scores on multivariate analysis (regression coefficient (95% confidence interval), −9.37 (−13.43–−5.32) and −10.22 (−13.74–−7.40), respectively, p < 0.0001 for both). At 6 months postoperatively, patients who stopped smoking within 1 year preoperatively (stopped smoking within 1 year vs. remote or never smokers, 41.0 ± 10.5 vs. 48.6 ± 7.2, p = 0.002), had lower performance status (0 vs. 1–2, 49.3 ± 6.6 vs. 38.6 ± 9.6, p < 0.0001), lived alone (living alone vs. living with somebody, 41.6 ± 9.7 vs. 48.1 ± 7.9, p = 0.021), and had higher comorbid burden (Charlson comorbidity index <3 vs. ≥3, 48.2 ± 6.9 vs. 39.1 ± 14.7, p = 0.003) had significantly worse physical quality of life scores on univariate analysis. More recent smoking (regression coefficient (95% confidence interval), −4.90 (−8.78–1.0), p = 0.014), lower performance status (8.90 (5.10–12.70), p < 0.0001), living alone (5.76 (1.39–10.13), p = 0.01), and higher comorbid burden (−6.94 (−11.78–−2.10), p = 0.006) were significant independent predictors of worse postoperative physical quality of life on multivariate analysis. Therefore, patients with these conditions might need additional support to maintain their physical condition after anatomical lung cancer surgery. [ABSTRACT FROM AUTHOR]

Antibody‐secreting cells (ASCs) produce immunoglobulin (Ig) G and IgE autoantibodies in secondary lymphoid organs. Evidence also suggests their existence in the skin in various chronic inflammatory conditions, and in association with CXCL12 and CXCL13, they regulate the recruitment/survival of ASCs and germinal center formation to generate ASCs, respectively. However, the presence of IgG and IgE in bullous pemphigoid (BP) lesions needs to be addressed. Here, we aimed to analyse BP skin for the presence of IgG and IgE and the factors contributing to their generation, recruitment, and persistence. Skin samples from 30 patients with BP were stained to identify ASCs and the immunoglobulin type they expressed. The presence of tertiary lymphoid organ (TLO) elements, which generate ASCs in non‐lymphoid tissues, and the chemokines CXCL12 and CXCL13, which regulate the migration/persistence of ASCs in lymphoid tissues and formation of TLOs, respectively, were evaluated in BP skin. BP skin harboured ASCs expressing the two types of antibodies IgG and IgE. ASCs were found in high‐grade cellular aggregates containing TLO elements: T cells, B cells, CXCL12+ cells, CXCL13+ cells and high endothelial venules. IgG+ ASCs were detected among these aggregates, whereas IgE+ ASCs were dispersed throughout the dermis. CXCL12+ fibroblast‐like cells were located close to ASCs. The inflammatory microenvironment of BP lesions may contribute to the antibody load characteristic of the skin of patients with BP by providing a site for the presence of ASCs. CXCL13 and CXCL12 expression may contribute to the generation and recruitment/survival of ASCs, respectively. [ABSTRACT FROM AUTHOR]

Fabricates a dipole particle suspension device by sandwiching rodlike TiO[sub x]N[sub y] particles. Attribution of the transmittance change to large absorption coefficient of the particle; Reason for the decrease in particle numbers taking part in light absorption; Observation of the particle chain formation along the electric field.

Anti‐N‐methyl‐D‐aspartate (NMDA) receptor encephalitis is a rare but occasionally fatal limbic encephalitis that may be accompanied by ovarian teratoma. Since the neuroglial tissue within the teratoma may be involved in the pathogenesis of this encephalitis, we attempted morphological and immunohistochemical characterization of the neuroglial tissue in four cases of ovarian teratoma associated with anti‐NMDA receptor encephalitis and 12 control cases, i.e., six consecutive cases of immature teratoma and six cases of mature teratoma with an abundant neuronal component, focusing mainly on NMDA receptor‐expressing neurons. NMDA receptor‐expressing neurons, being observed in all of the cases analyzed, were significantly densely aggregated (P = 0.030, Wilcoxon test) and relatively smaller in size in the encephalitis‐associated cases than in the control cases, and the Ki‐67 labeling index of neuroglial cells with these neurons was significantly higher in the encephalitis‐associated cases (P = 0.004, Wilcoxon test). In the cases with encephalitis, aggregation of B‐cells within or around the neuroglial tissue was also observed. Our present findings may be useful for more accurate diagnosis of anti‐NMDA receptor encephalitis and contribute to a better understanding of the pathogenesis. [ABSTRACT FROM AUTHOR]

Presents a study which described the performances of a switchable glazing of the shear stress-type dipole particle chain in elastomer (SS-type DPC). Experimental procedures; Results of the study; Conclusions.

Methotrexate, skin ulcer, extranodal NK/T-cell lymphoma, , Epstein-Barr virus Keywords: extranodal NK/T-cell lymphoma; ; methotrexate; Epstein-Barr virus; skin ulcer EN extranodal NK/T-cell lymphoma methotrexate Epstein-Barr virus skin ulcer 849 852 4 11/11/22 20221201 NES 221201 I Sir, i Immunosuppressive therapies such as methotrexate (MTX) can cause oligoclonal or monoclonal lymphoproliferative disorder, which is categorized as other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) in the current WHO classification.1 Most MTX-associated LPDs, including skin lesions, are of B-cell lineage, and only four cases of primary cutaneous MTX-associated T-cell LPD have been reported.2,3 The histologic subtypes of these four cases were angioimmunoblastic T-cell lymphoma, primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and MTX-associated T-cell LPD (not further specified), all of which regressed after MTX was discontinued. 4 Yu WW, Hsieh PP, Chuang SS. Cutaneous EBV-positive T-cell lymphoma vs. extranodal NK/T-cell lymphoma: a case report and literature review. [Extracted from the article]

(B) JXG histiocytes showed high-intensity nuclear expression of preferentially expressed antigen in melanoma (PRAME) but not cytoplasmic expression (PRAME, ×400). Preferentially expressed antigen in melanoma (PRAME) is an important modulator of nuclear retinoic acid receptor (RAR) signaling that promotes cell proliferation and survival.[1] RARs heterodimerize with retinoid X receptors to regulate the expression of various proteins, including those involved in lipid metabolism.[2] However, in neoplastic and non-neoplastic sebocytes, PRAME is expressed in the cytoplasm.[[3], [5]] The biological mechanism underlying cytoplasmic PRAME expression in these cells remains unknown but cross-reactivity between PRAME and an unknown lipid-associated protein is thought to be a possible explanation for this observed staining pattern.[3] Thus, we examined PRAME expression patterns in lipid-laden and non-lipid-laden histiocytes to investigate whether cross-reactivity with lipid droplet-coating proteins causes cytoplasmic PRAME staining and whether PRAME can be used as a marker for lipid-laden histiocytes. DISCUSSION In this study, nuclear PRAME expression was observed in some of the tested samples; however, cytoplasmic expression was not observed in either lipid-laden or non-lipid-laden histiocytes, suggesting that PRAME expression does not cross-react with lipid-droplet-coating proteins. [Extracted from the article]

A 39‐year‐old man had an intracranial tumour without infiltration into the surrounding cerebral tissue. The tumour recurred seven times in 11 years but maintained a well‐demarcated character. Histopathological examination of the 4th surgical specimens showed nests of tumour cells surrounding small blood vessels. The tumour cells harboured amphophilic cytoplasm and small round nuclei with fine chromatin, and perinuclear haloes and clear borders were frequently observed, which was unclassifiable histology. By the Deutsches Krebsforschungszentrum methylation classifier, the tumour was not classified into any of the methylation classes. mRNA sequencing identified a novel SREBF1::NACC1 gene fusion. This intracranial tumour could be a novel tumour entity with NACC1 rearrangement showing characteristic histological and diagnostic imaging findings. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common adult brain tumour, representing a high degree of malignancy. Transcription factors such as RUNX1 are believed to be involved in the malignancy of glioblastoma. RUNX1 functions as an oncogene or tumour suppressor gene with diverse target genes. Details of the effects of RUNX1 on the acquisition of malignancy in glioblastoma remain unclear. Here, we show that RUNX1 downregulates p21 by enhancing expressions of BIRC5 and PIF1, conferring anti-apoptotic properties on glioblastoma. A gene switch-off therapy using alkylating agent-conjugated pyrrole-imidazole polyamides, designed to fit the RUNX1 DNA groove, decreased expression levels of BIRC5 and PIF1 and induced apoptosis and cell cycle arrest via p21. The RUNX1-BIRC5/PIF1-p21 pathway appears to reflect refractory characteristics of glioblastoma and thus holds promise as a therapeutic target. RUNX gene switch-off therapy may represent a novel treatment for glioblastoma. Interfering with RUNX family proteins reduces glioblastoma growth in mice and reveals pathways involved in the maintenance of tumour growth. [ABSTRACT FROM AUTHOR]

Malignancy of medulloblastoma depends on its molecular classification. Sonic Hedgehog (SHH)-type medulloblastoma with p53 mutation was recognized as one of the most aggressive types of tumors. We developed a novel drug, chlorambucil-conjugated PI-polyamides (Chb-M′), which was designed to compete with the RUNX consensus DNA-binding site. Chb-M′ specifically recognizes this consensus sequence and alkylates it to inhibit the RUNX transcriptional activity. In-silico analysis showed all the RUNX families were upregulated in the SHH-type medulloblastoma. Thus, we tested the anti-tumor effects of Chb-M′ in vitro and in vivo using Daoy cell lines, which belong to SHH with p53 mutation. Chb-M′ inhibited tumor growth of Daoy cells by inducing apoptosis. The same inhibitory effect was also observed by knocking down of RUNX1 or RUNX2 , but not RUNX3. Apoptosis array analysis showed that Chb-M′ treatment induced phosphorylation of p53 serine 15 residues. In a subcutaneous tumor model, intratumoral injection of Chb-M′ induced tumor growth retardation. Chb-M' mediated inhibition of RUNX1 and RUNX2 can be a novel therapeutic strategy for SHH-type medulloblastoma with p53 mutation. • RUNXs were significantly highly expressed in SHH medulloblastoma. • Chb-M′ inhibits growth of SHH-type medulloblastoma with p53 mutation. • Knocking down of RUNX1 or RUNX2 retards proliferation of medulloblastoma. • Chb-M′ can be a novel drug for the SHH-type medulloblastoma with p53 mutation. [ABSTRACT FROM AUTHOR]

NKp46 (natural cytotoxic receptor 1/ CD335) is expressed on natural killer cells and Th2-type innate lymphocytes. However, NKp46 expression in human mast cells has not yet been reported. Here, we explored the expression of, and possible role played by, NKp46 in such cells. NKp46 protein was expressed in human mast cells in urticaria pigmentosa principally of the tryptase-positive/chymase-negative type ( MCT), but not in human non-neoplastic skin mast cells of the tryptase-positive/chymase-positive ( MCTC) type. NKp46 expression was also evident in the human neoplastic mast cell line HMC1.2. NKp46 knockdown changed the phenotype of this cell line from MCT to MCTC and downregulated GrB production, but did not influence IL-22 production. An agonistic anti- NKp46 antibody upregulated production of GrB and IL-22, but did not change the MCT-like phenotype of HMC1.2 cells. NKp46 was thus involved in the production of serine proteases and IL-22 in human mast cells. [ABSTRACT FROM AUTHOR]

Https://doi.org/10.1093/bjd/ljac008 Dear Editor, Interleukin (IL)-13 is one of the key cytokines of atopic dermatitis (AD), inciting skin inflammation and contributing to the disease's immunohistopathological features. At baseline, the cell densities of ICOS SP + sp ILCs, basophils and Th2 cells in lesional skin were significantly higher than in nonlesional skin (Figure 1a). [Extracted from the article]

Abstract: At the calibration of standard leaks by a comparison method with reference standard leaks, important factors to evaluate the flow rates are the degrees of stability of a mass spectrometer leak detector (MSLD) and standard leaks. Stability of two leak element type standard leaks, a glass and a plastic, are tested. The test indicates that the warming up time is mainly influenced by the temperature of the mass spectrometer and 2h is required to obtain a stabilized reading for the tested MSLD. In case of the glass type leak, 1h pumping is required to obtain the stabilized flow rate after the exposure to the ambient air. In case of the plastic type leak, 1min pumping is enough for the exposure time below 1h but 6h pumping is required after the 7days exposure. After the valve closed duration within 3h, the flow rates from both type of leaks recovered within a minute to 100%±0.5% of the averaged reading before the valve closed. [Copyright &y& Elsevier]

Abstract: A new leak element using a sintered stainless steel filter with a pore size of less than 1μm has been developed for in-situ calibrations of ionization gauges (IGs) and quadruple mass spectrometers (QMSs). The gas flow through this leak element realizes molecular flow at an upstream pressure of less than 104 Pa. This new leak element, which is a kind of open-type standard leak, has four advantages. (1) Calibrations for various gas species are available only with this single leak element because the conductance is easily compensated for gas species by molecular mass. (2) Calibrations with multiple pressure points are easily available because the conductance is constant against changing upstream pressure. (3) Calibrations for a gas mixture are available because the interference effect between gas molecules in a gas mixture is negligible. (4) The dependence of flow rate on temperature is small and is compensated theoretically. These advantages were experimentally demonstrated. The stability and uncertainty of the leak element were also evaluated. The changes in the conductance of this leak element were less than 3% over one year. Since the conductance is typically 10−10 ·m3/s, the reference gas flow in the range from 10−8 Pa·m3/s to 10−6 Pam3 is obtained by changing the upstream pressure from 102 Pa to 104 Pa with an uncertainty of approximately 6%. [Copyright &y& Elsevier]

The neonatal Fc receptor (FcRn) plays a role in trafficking IgG and albumin and is thought to mediate intravenous immunoglobulin (IVIG) therapy for certain diseases. IVIG can be used for the treatment of human Langerhans cell histiocytosis (LCH); however, the mechanism remains unclear. The expression and function of FcRn protein have not been studied in LCH, though the expression of FcRn messenger RNA (mRNA) have been reported. In this report, we confirmed the expression of FcRn in 26 of 30 pathological cases (86.7%) diagnosed immunohistochemically as LCH. The expression was independent of age, gender, location, multi‐ or single‐system, and the status of BRAFV600E immunostaining. We also confirmed the expression of FcRn mRNA and protein in the human LCH‐like cell line, ELD‐1. FcRn suppressed albumin consumption and growth of IVIG preparation‐treated ELD‐1 cells, but not of IVIG preparation‐untreated or FcRn‐knockdown ELD‐1 cells. In addition, FITC‐conjugated albumin was taken into Rab11‐positive recycle vesicles in mock ELD‐1 cells but not in FcRn‐knockdown ELD‐1 cells. IVIG preparation prolonged this status in mock ELD‐1 cells. Therefore, ELD‐1 recycled albumin via FcRn and albumin was not used for metabolism. Our results increase our understanding of the molecular mechanism of IVIG treatment of LCH. [ABSTRACT FROM AUTHOR]

Among several mechanisms for the resistance of human epidermal growth factor receptor 2-overexpressing (HER2 +) cancer cells to trastuzumab, little is known regarding the mechanism underlying the resistance to trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Cell death due to ADCC is caused by apoptosis of target cells induced by granzymes released from natural killer cells. Because optimal granzyme physiological activity occurs at neutral pH, we assumed that the pH of the intracellular environment influences the cytotoxic effects of granzymes. We established ADCC-resistant cells and compared them with wild-type cells in terms of the expression of intracellular pH-regulating genes. The expression of ATP6V1B1, which encodes a component of vacuolar ATPases, was downregulated in the ADCC-resistant cells. Thus, to functionally characterize ATP6V1B1, we used a CRISPR/Cas9 system to generate ATP6V1B1-knockout SKBR3 and JIMT-1 cells (both HER2 + human breast cancer cell line). The resulting cells exhibited significantly less ADCC than the control SKBR3 and JIMT-1 cells. The intracellular pH of the ATP6V1B1-knockout SKBR3 and JIMT-1 cells was significantly lower than control SKBR3 and JIMT-1cells. An analysis of granzyme dynamics during the ADCC reaction in cancer cells revealed that granzymes degraded intracellularly in the control SKBR3 and JIMT-1 cells and accumulated in ATP6V1B1-knockout cells, but were not cytotoxic. These findings suggest that decreased vacuolar ATPase activity alters the cytoplasmic pH of cancer cells to create an environment that is less suitable for granzyme bioactivity, which adversely affects the induction of apoptosis of cancer cells by NK cells. [ABSTRACT FROM AUTHOR]

Killer immunoglobulin-like receptor (KIR) 2DL4 (CD158d) was previously thought to be a human NK cell-specific protein. Mast cells are involved in allergic reactions via their KIT-mediated and FcɛRI-mediated responses. We recently detected the expression of KIR2DL4 in human cultured mast cells established from peripheral blood of healthy volunteers (PB-mast), in the human mast cell line LAD2, and in human tissue mast cells. Agonistic antibodies against KIR2DL4 negatively regulate the KIT-mediated and FcɛRI-mediated responses of PB-mast and LAD2 cells. In addition, agonistic antibodies and human leukocyte antigen (HLA)-G, a natural ligand for KIR2DL4, induce the secretion of leukemia inhibitory factor and serine proteases from human mast cells, which have been implicated in pregnancy establishment and cancer metastasis. Therefore, KIR2DL4 stimulation with agonistic antibodies and recombinant HLA-G protein may enhance both processes, in addition to suppressing mast-cell-mediated allergic reactions. [ABSTRACT FROM AUTHOR]

Tomiyasu et al. report a possible case of maculopapular eruption associated with G/P treatment. Since G/P treatment is widely used because of its efficacy and safety, clinical dermatologists should be aware that G/P may cause cutaneous drug eruption mediated by allergic responses. [Extracted from the article]

Signaling lymphocytic activation molecule family member 8 (SLAMF8) / B-lymphocyte activator macrophage expressed/CD353 is a member of the CD2 family. SLAMF8 suppresses macrophage function but enhances the growth of neoplastic mast cells via SHP-2. In this study, we found that some anaplastic large cell lymphoma (ALCL) samples were immunohistochemically positive for SLAMF8. However, we found no significant differences between SLAMF8-positive and SLAMF8-negative ALCL samples with respect to age, gender, site, or prognosis. We also identified SLAMF8 expression in ALCL cell lines, Karpas299, and SU-DHL-1. SLAMF8 knockdown decreased the activation of SHP-2 and the growth of these cell lines, and increased the apoptosis of these cell lines. In addition, we observed the interaction between SLAMF8 and SHP-2 in these cell lines using the DuoLink in situ kit. Taken together, these results suggest that SLAMF8 may enhance the growth of ALCL via SHP-2 interaction. [ABSTRACT FROM AUTHOR]

Activation-induced cytidine deaminase (AID) plays important roles in the development of diffuse large B-cell lymphoma (DLBCL); however, its prognostic value remains controversial. Here, we evaluated AID expression in 71 DLBCL patients treated with R-CHOP by immunohistochemistry and investigated its prognostic significance. AID expression was detected in 40.8% of DLBCL samples and associated with IRF4 expression. Notably, AID expression correlated with shorter progression-free survival and overall survival for patients with high (3-5) international prognostic index (IPI) score. Moreover, it was a strong predictor of poor overall response to salvage therapy after relapse or disease progression, which may suggest its role in promoting the evolution of tumors into highly refractory disease at relapse. Our findings indicate that AID expression effectively discriminates between IPI-high score patients with different survival outcomes, and suggest that initial disease control would be particularly important for the treatment of IPI-high score patients with AID-positive DLBCL. [ABSTRACT FROM AUTHOR]

Aims: GATA6 is known to play a role in lung development. However, its role in the carcinogenesis of lung cancer is not well studied. The aim of this study was to analyse GATA6 expression in lung adenocarcinomas (LAs) by immunohistochemistry (IHC) in order to define its association with clinicopathological characteristics. Methods and results: IHC analysis of GATA6 was performed with tissue microarray slides containing 348 LAs. The association between GATA6 expression and clinicopathological parameters was evaluated. GATA6 expression in epithelial tumours other than lung cancer was also evaluated. GATA6 expression was found in 47 LAs (13.5%). This occurred more frequently in younger patients (P = 0.005), and was associated with the absence of lymph node metastasis (P =0.024), well‐differentiated to moderately differentiated tumours (P < 0.001), the absence of lymphatic invasion (P = 0.020), and the absence of vascular invasion (P = 0.011). GATA6 expression was associated with mucin production (P < 0.001), the invasive mucinous adenocarcinoma subtype (P < 0.001), KRAS mutations (P = 0.026), expression of MUC2 (P < 0.001), CDX2 (P = 0.049), and MUC5AC (P < 0.001), and absence of expression of TTF‐1 (P = 0.002). GATA6 expression was also associated with hepatocyte nuclear factor 4α (HNF4α) expression (P < 0.001). GATA6 expression tended to indicate better prognoses, whereas patients with HNF4α expression had significantly worse prognoses (P = 0.033). Of 270 tumours other than lung cancer, 110 expressed GATA6. Conclusions: These findings suggest that GATA6 might interact with HNF4α and contribute to the development of mucinous‐type LAs. [ABSTRACT FROM AUTHOR]

Abstract: The signalling lymphocytic activation molecule family member 8 (SLAMF8)/CD353 is a member of the CD2 family of proteins. Its ligand has not been identified. SLAMF8 is expressed by macrophages and suppresses cellular functions. No study has yet explored SLAMF8 expression or function in human mastocytosis, which features oncogenic KIT‐mediated proliferation of human mast cells. SLAMF8 protein was expressed in human mastocytosis cells, immunohistochemically. SLAMF8 expression was also evident in the human mast cell lines, HMC1.2 (expressing oncogenic KIT) and LAD2 (expressing wild‐type KIT) cells. SLAMF8 knock‐down significantly reduced the KIT‐mediated growth of HMC1.2 cells but not that of LAD2 cells. SLAMF8 knock‐down HMC1.2 cells exhibited significant attenuation of SHP‐2 activation and oncogenic KIT‐mediated RAS‐RAF‐ERK signalling. An interaction between SLAMF8 and SHP‐2 was confirmed in HMC1.2 cells and all pathological mastocytosis specimens examined (19 of 19 cases, 100%). Thus, SLAMF8 is involved in oncogenic KIT‐mediated RAS‐RAF‐ERK signalling and the subsequent growth of human neoplastic mast cells mediated by SHP‐2. SLAMF8 is a possible therapeutic target in human mastocytosis patients. [ABSTRACT FROM AUTHOR]

Background: The use of video-assisted thoracoscopic surgery (VATS) has substantially increased in recent years. These procedures involve the insertion of specialized devices into the thoracic cavity via access ports. However, conventional devices such as cotton-tipped applicators and graspers can limit the field of view and injure the fragile lung tissue. The aim of this study was to develop a novel lung-stabilizing device for VATS that provides a good surgical field of view without causing lung injury.Methods: We developed a novel suction-based lung-stabilizing device equipped with three hemispheric 20-mm-diameter silicon suction cups. The utility and safety of the novel device were evaluated using a resected pig lung and canine models. In order to assess potential organ damage arising from the use of the novel device, canine lung parenchyma and pleura were macroscopically and microscopically examined after the device had been continuously applied under negative pressure conditions of -400 or -540 mmHg for 1 h.Results: To assess the utility of the novel device, we performed lobectomies in the resected pig lung and VATS in canine models. The device demonstrated sufficient power to stabilize the lungs and provided a clear field of view during surgery, which enabled us to perform VATS lobectomies more easily than conventional stabilizing forceps. Assessment of the dogs' lungs immediately after detaching the suction-based device revealed no complications such as hemorrhage, air leaks, and bullae formation. Pathological examination after 7 days also showed no substantial damage, except for a small impression in the parenchyma and pleura of the surface layer where the device had contacted the lung tissue.Conclusions: Although further validation studies in clinical settings are required, our study indicates that the novel lung-stabilizing device has potentially useful applications in VATS procedures. [ABSTRACT FROM AUTHOR]

Neuropilin-1 (NRP-1)-expressing macrophages are engaged in antitumor immune functions via various mechanisms. In this study, we investigated the role of NRP-1 on macrophages in antibody-mediated tumoricidal activity. Treatment of macrophages with NRP-1 knockdown or an anti-NRP-1-neutralizing antibody significantly suppressed antibody-dependent cellular cytotoxicity and modulated cytokine secretion from macrophages in vitro. Furthermore, in vivo studies using a humanized mouse model bearing human epidermal growth factor receptor-2 (HER2)-positive breast cancer xenografts showed that antibody-mediated antitumor activity and tumor infiltration of CD4 T lymphocytes were significantly downregulated when peripheral blood mononuclear cells in which NRP-1 was knocked down were co-administered with an anti-HER2 antibody. These results revealed that NRP-1 expressed on macrophages plays an important role in antibody-mediated antitumor immunity. Taken together, the induction of NRP-1 on macrophages may be a therapeutic indicator for antibody treatments that exert antibody-dependent cellular cytotoxicity activity, although further studies are needed in order to support this hypothesis. [ABSTRACT FROM AUTHOR]

Aims An easy and rapid assay for detecting mRNA in formalin-fixed paraffin-embedded samples [ RNA in-situ hybridization ( ISH)] has been reported recently. The aim of this study was to investigate the diagnostic accuracy of RNA ISH in detecting lung adenocarcinoma ( LA) with anaplastic lymphoma kinase ( ALK) gene rearrangement. Methods and results We tested ALK RNA ISH on 11 resected LAs for which ALK fusion was confirmed by immunohistochemistry ( IHC) and/or fluorescence in-situ hybridization ( FISH). ALK mRNA expression was detected by RNA ISH in all 11 ALK-positive LAs, with a mean positive cell proportion of 68.4% (median, 75.3%; range, 3-98.8%), by counting 100 tumour cells at 10 different loci; RNA ISH did not detect ALK mRNA expression in the normal surrounding lung cells. Next, we explored the concordance between ALK RNA ISH and IHC/ FISH tests by using tissue microarrays ( TMAs) containing 294 LAs. In the TMA slides, we found five ALK-positive cases with IHC and/or FISH. The mean proportion of ALK RNA ISH-positive cells in these five cases was 75.6% (median, 82%; range, 40-94%), whereas the proportion of ALK RNA ISH-positive cells in the remaining 289 cases was 0.3% (median 0%; range, 0-15%). When the cutoff value was set at 15%, ALK RNA ISH-positive and ALK RNA ISH-negative cases were distinguishable with 100% sensitivity and specificity relative to the IHC/ FISH tests. Conclusions Our findings show that RNA ISH is useful for detecting ALK rearrangement with high sensitivity and specificity relative to conventional IHC/ FISH tests. Thus, RNA ISH, which is an easy and rapid assay, could be an alternative method to IHC and FISH. [ABSTRACT FROM AUTHOR]

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in a number of tumor cell types. The immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing isoforms of this molecule which possess a long cytoplasmic tail (CEACAM1-L) generally play inhibitory roles in cell function by interacting with Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 and/or SHP-2. Src family kinases (SFKs) are also known to bind to and phosphorylate CEACAM1-L isoforms. Here, we report that CEACAM1 was uniquely expressed at high levels in both human neoplastic mast cells (mastocytosis) and medullary thyroid carcinoma cell (MTC) lines, when compared with their expression in nonneoplastic mast cells or nonneoplastic C cells. This expression was mainly derived from CEACAM1-L isoforms based upon assessment of CEACAM1 mRNA expression. CEACAM1 knockdown upregulated cell growth of HMC1.2 cells harboring KIT mutations detected in clinical mastocytosis, whereas downregulated the growth of TT cells harboring RET mutations detected in clinical MTCs. Immunoblotting, ELISA and immunoprecipitaion analysis showed that activated SHP-1 is preferentially associated with CEACAM1 in HMC1.2 cells harboring KIT mutations, whereas Src family kinases (SFKs) are preferentially associated with CEACAM1 in TT cells harboring RET mutations. These studies suggest that the dominantly interacting proteins SHP1 or SFK determine whether CEACAM1-L displays a positive or negative role in tumor cells. [ABSTRACT FROM AUTHOR]

Aims The lipogenic pathway is up-regulated in proliferating cells. However, the clinical impact of neoplastic steatogenesis in lung cancer is unclear. The aim of the present study was to evaluate the association of intracytoplasmic lipids with the clinicopathological features of lung adenocarcinoma (ADC), by immunohistochemical analysis of adipophilin (ADP), a coating protein found on intracytoplasmic lipid droplets. Methods and results Tissue microarrays consisting of 328 primary lung ADCs surgically resected at Kyoto University Hospital were immunostained for ADP. Subsequently, correlations between ADP expression and clinical, molecular and survival data were performed. Fifty-one (15.5%) cases were ADP-positive. The presence of vascular invasion ( P = 0.003), predominantly solid histology ( P < 0.001), poorly differentiated type ( P < 0.001), wild-type EGFR ( P = 0.002), ALK fusion ( P < 0.001), strong/diffuse mitochondrial staining ( P < 0.001), a lack of surfactant protein B expression ( P = 0.014) and a high Ki67 index ( P < 0.001) were significantly correlated with ADP-positive ADC. In contrast, there were no correlations between ADP-positive ADC and sex, age, smoking history, tumour stage, thyroid transcription factor-1 expression, or KRAS mutational status. ADP-positive ADCs had apocrine-like features ( P < 0.001). Patients with ADP-positive ADC had worse disease-free and overall survival ( P = 0.047 and P = 0.013, respectively) than those with ADP-negative ADC. Conclusions ADP was expressed in a small proportion of lung ADCs. ADP-positive lung ADC was significantly associated with apocrine-like features, wild-type EGFR, and poor prognosis, suggesting that ADP-positive lung ADC could be a distinct subtype of lung adenocarcinoma, induced by up-regulation of the lipogenic pathway. [ABSTRACT FROM AUTHOR]

Current development of fluorine doped tin oxide (FTO) films for the enhancement of light trapping is limited by the tradeoff between roughness and transmittance, since none of them can be improved without sacrificing the other. In this study, we report increases in roughness from 13 to 60 nm and haze from 1.2 to 10.3% for FTO films with a thickness of only 300 nm, by inclusion of different additives into the deposition system. Such significant improvements are achieved whilst maintaining a low resistivity and high transmittance. This results from the development of the desired pyramidal grain morphology associated with the strengthening of (110) preferred orientation and concurrent weakening of (200) and/or (301) preferred orientations. Thus, our study provides a general strategy for developing morphology-controlled FTO films to be compared with current commercial ones with a roughness of 38 nm and a thickness of 800 nm, for improving the light trapping and thus the efficiency of solar cells. [ABSTRACT FROM AUTHOR]

Abstract: Stability tests of two quadrupole mass spectrometers (QMSs) were performed using a two-stage flow-dividing system from the following viewpoints: (1) fluctuation and drift of ion current, (2) repeatability of ion current, (3) change in ion current owing to prior conditions of use, (4) long-term stability of sensitivity, and (5) interference effect. These tests were performed at the pressure from 8 × 10−6 Pa to 8 × 10−4 Pa using N2, Ar, He, and H2. The fluctuation and drift of two QMSs over 1 h were within 2%. The repeatabilities at pressures of 8 × 10−6 Pa and 8 × 10−5 Pa were within 2% during eight cycles with an interval of 1 h between each cycle. However, the repeatability at 8 × 10−4 Pa increased to be within 4%. The changes in sensitivities of QMS-1 and QMS-2 for 757 days were less than ±15% and less than ±25%, respectively. The change owing to the interference effect was less than 2% while the partial pressure of the interference gas was under 2 × 10−4 Pa. However, both positive and negative changes were observed less than 60% with increasing the partial pressure of the interference gas until 8 × 10−3 Pa. [ABSTRACT FROM AUTHOR]

Abstract: Stability tests of four ionization gauges (a BA gauge, an extractor gauge, an AT gauge, and a BA gauge with a heating electrode) were performed using a two-stage flow-dividing system from four viewpoints: (1) the fluctuation and drift of pressure readings, (2) the repeatability of pressure readings, (3) the change in sensitivity owing to prior conditions of use and (4) long-term stability. These tests were performed at pressures from 8×10−6 Pa to 8×10−4 Pa using N2 gas under tightly controlled conditions. The fluctuation and drift of the four IGs were within 1% over 1h. Their repeatability was also within 1% during eight cycles with an interval of 1h between each cycle. Although changes in sensitivity of several percent owing to prior conditions of use were observed, the sensitivity was recovered to within 1% of its original values after operation in ultrahigh vacuum for one day. The result of a long-term stability test over a year showed that the sensitivity of the four IGs tended to decrease by 2.6–5.4% due to aging, depending on the gauge. [Copyright &y& Elsevier]

Abstract: For the realization of an accurate vacuum standard by the orifice-flow method in high and ultra-high vacuum, it is important to determine the conductance of an orifice accurately. Since the shape of the edge of the orifice significantly influences the conductance, a new orifice with thin tapered edge was designed and fabricated to measure its dimension and shape precisely with microscopy techniques. The area of the aperture was determined with the relative standard uncertainty, u r, of 0.011% from the diameter measurement. The transmission probability, W, was estimated with u r of 0.039% using a Monte Carlo calculation from the geometry. Influences of a deviation from cosine distribution of incident molecules due to the geometry of a vacuum chamber and the specular reflection at the orifice edge on the value of W were also discussed. As a result, the conductance was calculated with u r of 0.041%. The main source of the uncertainty was that of W and originated from its geometry, which verifies that the measurement of orifice edge is important for the accurate evaluation of the conductance. [Copyright &y& Elsevier]

Background Signal transduction upon HER3/EGFR dimerization to PI3K/AKT/mTOR pathways are thought to be involved in cancer survival, proliferation and up-regulation of PD-L1 expression. It is therefore hypothesized that inhibition of HER3 signal could enhance anti-tumor immunity by regulating the expression of PD-L1. Methods Two patient-derived xenograft (PDX) models of breast cancer were evaluated with patritumab (anti-HER3 antibody), polyclonal activated autologous T cells (PATCs) or a combination of patritumab and PATCs (P-PATCs). Tumor size was measured for anti-tumor effects of each treatment. To test the immunological modulation by patritumab, tumors and liver tissue were immunohistochemically stained with anti-CD3, CD4, CD8, CD137 and PD-L1 antibody. Furthermore, quantitative real-time PCR and RNA-sequencing was performed on the tumor samples from the PDX models. Results Although treatment of PATCs or patritumab alone showed limited anti-tumor effects, P-PATCs treatment demonstrated a significantly greater anti-tumor response in both 2 PDX models. Interestingly, the proportion of CD137 expressing T cell infiltration was much higher in the P-PATCs group compared to the patritumab or PATCs group while the proportion of CD4+ T cell infiltration was also higher in P-PATCs group. There was an equal proportion of T cells without CD137 expression present in liver tissue in both PATCs and P-PATCs groups. Conclusions These data suggest that patritumab could help augmentation of antigen-specific T cell activation leading to additional anti-tumor effects on patritumab treatment alone by means of immunological mechanisms. Thus, patritumab treatment might become a novel treatment strategy for HER3/neuregulin (ligand for HER3)-expressing breast cancer patients in the future. [ABSTRACT FROM AUTHOR]

Signal transduction upon HER3/EGFR dimerization to PI3K/AKT/mTOR pathways are thought to be involved in cancer survival, proliferation and up-regulation of PD-L1 expression. It is therefore hypothesized that inhibition of HER3 signal could enhance anti-tumor immunity by regulating the expression of PD-L1. Two patient-derived xenograft (PDX) models of breast cancer were evaluated with patritumab (anti-HER3 antibody), polyclonal activated autologous T cells (PATCs) or a combination of patritumab and PATCs (P-PATCs). Tumor size was measured for anti-tumor effects of each treatment. To test the immunological modulation by patritumab, tumors and liver tissue were immunohistochemically stained with anti-CD3, CD4, CD8, CD137 and PD-L1 antibody. Furthermore, quantitative real-time PCR and RNA-sequencing was performed on the tumor samples from the PDX models. Although treatment of PATCs or patritumab alone showed limited anti-tumor effects, P-PATCs treatment demonstrated a significantly greater anti-tumor response in both 2 PDX models. Interestingly, the proportion of CD137 expressing T cell infiltration was much higher in the P-PATCs group compared to the patritumab or PATCs group while the proportion of CD4+ T cell infiltration was also higher in P-PATCs group. There was an equal proportion of T cells without CD137 expression present in liver tissue in both PATCs and P-PATCs groups. These data suggest that patritumab could help augmentation of antigen-specific T cell activation leading to additional anti-tumor effects on patritumab treatment alone by means of immunological mechanisms. Thus, patritumab treatment might become a novel treatment strategy for HER3/neuregulin (ligand for HER3)-expressing breast cancer patients in the future. [ABSTRACT FROM AUTHOR]

Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1/PD-L1 expression and CAS prognosis. CAS cases (n = 106) were immunohistochemically studied for PD-L1 and PD-1 expression, and the correlation with patient prognosis was analyzed. PD-L1 expression was assessed by flow cytometry on three CAS cell lines with or without IFNγ stimulation. A total of 30.2% of patients' samples were positive for PD-L1, and 17.9% showed a high infiltration of PD-1-positive cells. Univariate analysis showed a significant relationship between a high infiltration of PD-1-positive cells with tumor site PD-L1 expression and favorable survival in stage 1 patients (p= 0.014, log-rank test). Multivariable Cox-proportional hazard regression analysis also showed that patients with a high infiltration of PD-1-positive cells with tumor site PD-L1 expression were more likely to have favorable survival, after adjustment with possible confounders (hazard ratio (HR) = 0.38,p= 0.021, 95% confidence interval (CI) 0.16–0.86). Immunofluorescence staining of CAS samples revealed that PD-L1-positive cells were adjacent to PD-1-positive cells and/or tumor stroma with high IFNγ expression.In vitrostimulation with IFNγ increased PD-L1 expression in two out of three established CAS cell lines. Our results suggest that PD-1/PD-L1 expression is related to CAS progression, and the treatment with anti-PD-1 antibodies could be a new therapeutic option for CAS. [ABSTRACT FROM AUTHOR]